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A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression.

Original publication

DOI

10.1158/0008-5472.CAN-10-2693

Type

Journal article

Journal

Cancer Res

Publication Date

15/02/2011

Volume

71

Pages

1253 - 1262

Keywords

Amino Acid Sequence, Antigens, Neoplasm, Base Sequence, Cancer Vaccines, Cells, Cultured, Humans, K562 Cells, Melanoma, Melanoma-Specific Antigens, Models, Biological, Molecular Sequence Data, Neoplasm Metastasis, Neoplasm Proteins, Receptors, Antigen, T-Cell, alpha-beta, Remission Induction, Skin Neoplasms, T-Lymphocytes, Cytotoxic, Tissue Distribution, Tumor Burden